Hypersensitivity is the term applied when an adaptive immune response occurs in an inappropriate or exaggerated form causing tissue damage. Specifically, Type I, or immediate hypersensitivity occurs when the immune response is directed against antigens, such as pollen or house dust mite fecal particles. This Type I response is mediated through immunoglobulin E (IgE) interaction with mast cells and basophils. (IMMUNOLOGY, Roitt, I. M., et al., (eds.) C. V. Mosby Co., St. Louis, Mo., pp. 19.1-19.20 (1989)).
Mast cells and basophils express the high affinity Fc receptor for IgE, designated polyvalent FceRI. Once IgE binds to the Fc.epsilon., subsequent binding of allergen to the IgE molecules caues the receptors to cross-link, triggering the release of cytoplasmic secretory granules containing histamine, and other pharmacological mediators which produce an acute immune reaction (e.g., asthma, dermatitis or rhinitis).
The Fc.epsilon.RI receptor is a complex of three protein subunits, the .alpha., .beta. and .gamma. subunits. The .beta. and .gamma. subunits have an intracellular domain termed a "tyrosine activation motif" or TAM. TAM motifs and related tyrosine-containing motifs are found on a number of growth factor and primary immune response receptors. Phosphorylation of these motifs by protein tyrosine kinases is thought to play an integral role in receptor activation and cellular signal transduction. (Reth, M., Nature 338:383-384 (1989); Koch, C. A., et al., Science 252:668-674 (1991); Samuelson, L. E., and Klausner, R. D., J. Biol. Chem. 267:24913-24916 (1992)). It has also been shown that a second group of intracellular tyrosine kinases become physically associated with the activated (phosphorylated) receptors and are likely targets of receptor activity (i.e., phosphorylation by the receptor). Phosphorylation of these "second group" proteins initiates additional intracellular signal transduction events which activate biochemical processes within the cell. (Chan, A. C., et al., Cell 71:649-662 (1992); Chan, A. C., et al., Curr. Opin. Immunol. 4:246-251 (1992); Courtneid, S. A., et al., Cell Growth Differentiation 2:483-486 (1991)).
Thus, the protein-protein interaction of activated receptor protein and intracellular kinase protein plays a critical role in intracellular signal pathways. When these pathways are activated inappropriately, such as when the immune system responds to pollens and other allergens, upper respiratory symptoms of allergic rhinitis, wheezing and respiratory distress result. In a severe allergic reaction, life-threatening anaphylaxis can occur.
Currently, treatment of allergies includes avoidance of the allergen, such as the removal of pets from the home or the installation of elaborate air filtration systems to minimize airborne allergens. However, complete removal may be difficult such as when the allergen is ubiquitous as in the case of pollen and dust mites. Pharmacological agents, such as anti-histamines and steroids may also be used in treatment. However, these drugs often produce unwanted side effects, such as drowsiness and gastrointestinal distress. When complete removal of the allergen is impossible, and the allergy cannot be managed with drugs, hyposensitization therapy may be tried. Hyposensitization consists of repeated subcutaneous injections of gradually increasing doses of the responsible allergen. However, hyposensitization therapy is a painful and time-consuming process with unpredictable results. (HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 12th ed., Wilson, J. D., et al., eds., McGraw-Hill, Inc., New York, N.Y., pp. 1422-1428 (1991)). A significant need exists for materials useful in the design, screening and/or evaluation of effective therapeutic or preventive agents and methods for inhibiting inappropriate or exaggerated response of the immune system to allergens.